2015年肿瘤治疗资料集中贴

SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 03/19/15 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD), today announced it will present data on its investigational anti-cancer drugs at the annual meeting of the American Association for Cancer Research (AACR) 2015 being held April 18-22, 2015, in Philadelphia, Pennsylvania. The company will present clinical and preclinical data on TH-4000, its proprietary, hypoxia-activated irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which the company believes support its two planned Phase 2 proof-of-concept clinical trials of TH-4000. In addition, preclinical data evaluating the potential use of evofosfamide (previously known as TH-302) in a variety of tumor types will be presented by Threshold and Merck KGaA, Darmstadt, Germany, the company's partner for the development and commercialization of evofosfamide.

"We believe that the data we will present at AACR support our clinical development plans for TH-4000 in patients with tumors that are not candidates for conventional EGFR-TKI therapy," said Tillman Pearce, MD, Chief Medical Officer of Threshold. "In particular, we believe that the data support the development of TH-4000 in patients with mutant EGFR-positive non-small cell lung cancer (NSCLC) after conventional EGFR-TKI therapy has failed as well as in patients with head and neck cancer for which EGFR over-expression is associated with worse outcomes. Both tumor types have been shown to be highly hypoxic. TH-4000 is designed to release an irreversible EGFR-TKI under hypoxic conditions, which are commonly found in the tumor microenvironment. Preferential activation of TH-4000 in the hypoxic tumor microenvironment may provide the basis for achieving therapeutic doses of TKI while avoiding the skin and gastrointestinal toxicities associated with currently available EGFR-TKI therapies. We look forward to sharing these data at AACR and initiating our first planned Phase 2 trial of TH-4000 in patients with EGFR-positive, T790M-negative NSCLC shortly thereafter."

In collaboration with Threshold, data on TH-4000 will be presented by its co-inventors from The University of Auckland, Adam Patterson, Ph.D., and Jeff Smaill, Ph.D., on Wednesday, April 22, 8 AM - 12 PM EDT (Abstract #5358 in Poster Section #28) at the AACR annual meeting.

Additional Research on Evofosfamide in a Variety of Tumor Types

Threshold and Merck KGaA, Darmstadt, Germany, will present preclinical data related to evofosfamide in multiple tumor types.

"Evofosfamide is our most advanced hypoxia-activated prodrug in clinical development and has been evaluated in more than 1,500 patients with cancer to date," said Charles Hart, Ph.D., Senior Vice President of Biology at Threshold. "Our development strategy is to investigate the potential therapeutic application of evofosfamide across a variety of tumor types, and the preclinical data being presented at AACR highlight potential new therapeutic areas for further investigation."

Data being presented on evofosfamide include:

Association between Chk1 inhibitor AZD7762-mediated modulation of pharmacodynamic biomarkers and potentiation of hypoxia-activated prodrug TH-302 antitumor efficacy in a human tumor xenograft model (Abstract #2424, Poster Section #22, Monday, April 20, 1:00 PM - 5:00 PM EDT)
Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models (Abstract #2603, Poster Section #29, Monday, April 20, 1:00 PM - 5:00 PM EDT)
DNA repair processes involved with the hypoxia-activated prodrug TH-302: comparison to cisplatin and temozolomide (Abstract #3867, Poster Section #5, Tuesday, April 21, 1:00 PM - 5:00 PM EDT)
Hepatic hypoxia-activated intraarterial therapy: effect of selective targeting of hypoxia in a rabbit liver tumor model (Abstract #5271, Poster Section #23, Wednesday, April 22, 8:00 AM - 12:00 PM EDT)
TH-302 potentiates the antitumor activity of topotecan in neuroblastoma and rhabdomyosarcoma preclinical models (Abstract #5333, Poster Section #27, Wednesday, April 22, 8:00 AM - 12:00 PM EDT)
The abstracts are now published on the AACR website at http://www.aacr.org.
http://investor.thresholdpharm.c ... fm?ReleaseID=902417

Clinical data indicate that mutant EGFR NSCLC is often heterozygous (PLoS ONE 2013; 8: e54170; PLoS ONE 2009; 4: e7464) and the presence of wild type (WT) EGFR allele is associated with limited response to EGFR-tyrosine kinase inhibitor (TKI) therapy (Cancer Sci 2008; 99:929). Tumor hypoxia upregulates WT EGFR protein and its cognate ligand TGFα via several HIF-dependent mechanisms (reviewed in: Curr Pharm Des 2013; 19:907). NSCLC is known to be a hypoxic tumor, and thus hyperactivation of WT EGFR may be an important cause of resistance to EGFR-TKI therapy. TH-4000 (formerly called PR610) is a clinical-stage hypoxia-activated prodrug that releases an irreversible EGFR-TKI under hypoxic conditions and may overcome resistance to conventional TKI therapy. We tested this hypothesis using the heterozygous WT/Δ19 EGFR PC9 tumor model and found it to be resistant to clinically relevant doses of the EGFR-TKI erlotinib; 100% of tumors progressed during treatment with human matched plasma PK exposures of erlotinib. In contrast, the homozygous Δ19 mutant EGFR tumor HCC827 was readily controlled by erlotinib (100% tumor regression). TH-4000 (15 mg/kg) produced 100% tumor regressions in both models. In vitro, PC9 cells exposed to hypoxia had elevated EGFR protein and were more resistant to erlotinib as measured by EGFR phosphorylation. In nude mice, single-dose administration of 15 mg/kg TH-4000 achieved a plasma AUC equivalent to 32 mg/m2 in human subjects, one-fifth of the maximum tolerated dose (MTD) defined in the Phase 1 trial (MTD = 150 mg/m2/week; NCT01631279). A single dose of TH-4000 (15 mg/kg) cleared rapidly from mouse plasma (T&#189; = 0.37 h) but had durable residency in PC9 tumors (T&#189; = 39 h), releasing TKI above efficacious levels for 7 days (T&#189;β = 84 h). Consistent with these PK properties, tumor shutdown of EGFR signalling was durable, with no recovery by day 7. To confirm the mechanism of action, TH-4000 was shown to be metabolized efficiently under hypoxia using a panel of human NSCLC cell lines (rate of TKI release 0.4-2.1 nmol/hr/106 cells), a process that was inhibited by oxygen (TKI release < 0.002 nmol/hr/106 cells). Cellular anti-proliferative and receptor phosphorylation assays demonstrated a 14-80 fold reduction of TH-4000 activity relative to TKI. Using PC9 tumors, hyperbaric oxygen breathing suppressed release of TKI from TH-4000 by >80% (538 vs 99 nmol/kg; p <0.01) compared to air breathing controls. Collectively, these data further validate that TH-4000 is a hypoxia-activated irreversible EGFR-TKI, and show that TH-4000 has greater activity compared with erlotinib in a heterozygous xenograft model of mutant EGFR NSCLC. Thus, TH-4000 may overcome hypoxia-induced resistance to erlotinib at plasma exposures readily achieved in human subjects.
http://investor.thresholdpharm.c ... fm?ReleaseID=902417

都放在第一帖比較好..

感谢老马的信息！

看了论文，说是化疗间歇用靶向好些。。。。。俺家直接上的靶向。。。。

谢谢分享，努力消化。

http://www.astrazeneca.com/Media ... utm_campaign=buffer
18 to 22 April 2015.
Data being presented at the AACR annual meeting include:

Detail on three molecular subtypes of acquired resistance to AZD9291, AstraZeneca’s investigational medicine for patients with advanced non-small cell lung cancer, identified through cutting-edge plasma next generation sequencing (rapid whole genome sequencing of tumour DNA from blood samples) [Late breaker 123]. Data will highlight the need for combination therapies to effectively prevent or treat resistance and demonstrate the potential of the combination of AZD9291 with AstraZeneca’s investigational, highly potent and selective c-MET inhibitor, savolitinib (AZD6094, volitinib) [Abs761], as a therapeutic solution to these resistance mechanisms.
The medicinal chemistry behind the discovery of AZD9496, AstraZeneca’s novel, oral selective oestrogen receptor down-regulator (SERD), currently in Phase I development for patients with oestrogen receptor positive (ER+) breast cancer. The oral pharmacokinetic properties of AZD9496 will also be presented [Abs3650], demonstrating the significant pre-clinical tumour efficacy that supported its advance into clinical trials.
The PI3K/ AKT/ mTOR cellular pathway, which regulates cell growth and survival, is the most commonly mutated pathway in cancer. Data will be presented on compounds within AstraZeneca’s pipeline that inhibit key enzymes (kinases) on this pathway, including:

AZD2014 is a novel dual m-TORC1 and m-TORC2 inhibitor, currently in Phase II development in solid tumours. Preclinical data will be presented supporting the combination of AZD2014 with paclitaxel (chemotherapy) in solid tumours including ovarian and lung cancer [AbsCT138]. Phase I data will also be presented on the combination of AZD2014 with AstraZeneca’s treatment for advanced breast cancer, Faslodex (fulvestrant), in patients with ER+ advanced metastatic breast cancer [AbsCT233], demonstrating the advantage of intermittent versus continuous infusion of AZD2014 to avoid toxicity and give a favourable adverse event profile.
AZD8186 is a potent, oral inhibitor of PI3K isoforms beta and delta, currently in Phase I development in solid tumours. Clinical data will be presented from a dosing and safety study in PTEN deficient tumours carried out in collaboration with a number of partners including the Princess Margaret Cancer Centre, Toronto, The Royal Marsden Hospital, London and the Dana Farber Cancer Institute, Boston [AbsCT329]. PTEN is a natural inhibitor of the PI3K/ AKT/ mTOR pathway. Loss of PTEN, which is implicated in the development of a large number of cancers, can confer dependency on the PI3K beta form of PI3K.
AZD5363 is an inhibitor of three different forms of the AKT protein, currently in Phase II development in breast cancer. Phase I/II data will be presented on the combination of AZD5363 with paclitaxel [AbsCT331] in advanced or metastatic breast cancer, with cutting edge circulating tumour DNA analysis used as a surrogate for response and resistance. Phase I data will also be presented on AZD5363 in combination with Lynparza (olaparib) for advanced BRCA mutated cancer patients in a study designed to optimise drug exposures, minimise pharmacokinetic variability and reduce patient numbers needed for study [AbsCT323].
First generation compounds targeting the PI3K/AKT/mTOR pathway have experienced toxicity issues resulting in adverse events such as rash, diarrhoea and hyperglycaemia. Data from preclinical studies will also be presented at the AACR meeting demonstrating the potential of combinations of inhibitors across the pathway (AZD8186 with inhibitors of PI3K and mTOR) as an approach to achieve comprehensive PI3K pathway suppression in a range of PTEN protein deficient tumours [Abs4696], while limiting potential adverse events.

Pre-clinical data will also be presented on AZD8835, an inhibitor of both PI3Kalpha and PI3Kdelta in Phase I development in solid tumours, examining whether intermittent dosing can avoid adverse effects and overcome resistance [Abs2830; 2665].

DNA damage repair

AstraZeneca has one of the most extensive portfolios in the area of DNA damage repair, including the recently approved Lynparza (olaparib). Scientists from the UK Institute of Cancer Research, leading the TOPARP Phase II study (Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer) will present data in an oral late breaker session demonstrating the potential to identify biomarkers for patients who will respond well to olaparib through next generation sequencing of tumour biopsies [AbsCT322].

Susan Galbraith, Head of the Oncology Innovative Medicines Unit at AstraZeneca, said: “The extensive range of work we are presenting this year illustrates the pace of acceleration of our early-to-mid-stage pipeline, and its sharp focus on the science. For example, the PI3Kinase pathway is the most commonly mutated pathway in cancer. Our strategy is to develop highly specific inhibitors to the different PI3K isotypes and use them in intermittent dosing schedules which address the issue of pathway. Because we have compounds which work at each step of this pathway, we are able to use them in combinations which overcome elements of resistance and improve the risk benefit profile and efficacy compared with monotherapy for the benefit of patients. We are also presenting a number of examples of combinations across our portfolio, which is an important part of our strategy to develop more efficacious treatments for cancer.”

Immunotherapy

Immuno-oncology is a promising therapeutic approach that harnesses the patient’s own immune system to help fight cancer. AstraZeneca’s strategy is to develop novel combinations that target each of the escape mechanisms used by tumour cells to evade the immune system. Across preclinical and clinical development, the company’s robust immuno-oncology pipeline contains molecules that enhance antigen presentation to initiate an immune response to the tumour; molecules to enhance tumour destruction by T-cells (immune cells) and enhance immune cell memory; and compounds that target the tumour microenvironment.

At AACR AstraZeneca will describe molecules within its immuno-oncology pipeline that stimulate the OX40 receptor, which plays a key role in the survival and homeostasis of effector and memory T-cells, and cause T-cell activation, survival, proliferation and cytokine (small proteins that act as chemical ‘messengers’ between cells) release, all of which may help destroy cancer cells. Preclinical data will be presented to show that OX40 ligand fusion proteins, such as MEDI6383, induce potent T-cell proliferation, overcome regulatory T-cell suppression and promote anti-tumour activity in preclinical models as a single agent or in combination [Abs4275].

Yong-Jun Liu, M.D., Ph.D., Head of Research at MedImmune said: “Our comprehensive immuno-oncology pipeline allows us to address multiple immune pathways to explore the most effective treatment options for patients in an accelerated way. OX40 is one of the most exciting T-cell co-stimulatory receptors, critical for T-cell activation, expansion, effector T-cell function and T-cell memory maintenance. In addition, OX40 has the ability to block the function of both inducible and natural regulatory T-cells. We believe that the combination of OX40 agonists with checkpoint blockers and other co-stimulatory molecules and cytokines that target antigen presenting cells, innate immune cells and the cancer microenvironment will be key to achieving more successful cancer immunotherapy".

Antibody drug conjugates

Antibody-drug conjugates (ADCs) are anticancer drugs which combine the specificity of antibodies with the potent cancer cell killing properties of novel ‘warheads’. The antibody selectively targets cancer cells to deliver tumour-destroying warhead chemicals which are internalised into the cancer cell, avoiding damage to healthy tissue. MedImmune scientists will describe generation of a potent, novel antibody-drug conjugate that induces long-term tumour regression and has anticancer stem cell activity [Abs948]. However, resistance to ADCs can develop through a number of mechanisms, one of which is the increased expression of molecular ‘pumps’ inside the cancer cell, such as P-glycoprotein (P-gp), which pump the anti-cancer drug out before it can have an effect. Data will be presented at the AACR meeting showing how ADCs with different warheads (pyrrolobenzodiazepine dimer and tubulysin) are active in tumours with P-gp resistance [Abs3601].

OX40激动剂也只能做单抗吗？？

Olaparib Nears 90% Response in Molecular Subgroup of mCRPC
http://www.onclive.com/conferenc ... r-Subgroup-of-mCRPC
Treatment with the PARP inhibitor olaparib (Lynparza) demonstrated a durable overall response rate (ORR) of 87.5% in a biomarker-defined subgroup of men with pretreated sporadic metastatic castration-resistant prostate cancer (mCRPC) in a phase II multi-step adaptive trial. In the full population of the study, the ORR was 32.7%.
Results from the study, labeled TOPARP, were presented at the 2015 AACR Annual Meeting. In the first stage of the trial, labeled TOPARP-A, olaparib was administered to patients with unselected mCRPC, followed by preplanned genomic analysis using next-generation sequencing (NGS) to identify a biomarker-defined subgroup based on those who responded. Overall, the study found that patients with somatic or germline defects in DNA repair genes, such as BRCA2 and ATM, were more likely to respond to olaparib than those without the alterations, representing a unique molecularly-defined treatment population. “The data from TOPARP-A show that single-agent PARP inhibition with olaparib has durable antitumor activity in men with metastatic castration-resistant prostate cancer and identified a molecularly distinct subgroup of patients that respond to the drug,”
study author Joaquin Mateo, MD, clinical research fellow in the Prostate Targeted Therapy Group and Drug Development Unit at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in the United Kingdom (UK), said in a statement. “These are potentially the first clinical data supporting molecular stratification of treatment in prostate cancer, and we are testing this idea in the second stage of the TOPARP trial, TOPARP-B.” The first stage of the study enrolled 50 patients across 7 UK centers. All the patients had received prior treatment with docetaxel, 48 had received abiraterone (96%), and 29 had received cabazitaxel (58%). Patients received olaparib at a dose of 400mg twice daily continuously in a 28-day cycle. The primary endpoint of the study was ORR. The secondary endpoints for the study included safety, tolerability, progression-free survival (PFS), and overall survival (OS). In the full population of evaluable patients (n = 49), 16 (32.7%) responded to olaparib (95% CI: 20.0-47.5), six patients had radiological responses, as assessed by RECIST, and 11 patients had a biochemical response defined as a ≥50% decrease in PSA levels. NGS was conducted on fresh CRPC biopsies, taken before and during treatment with olaparib. Overall, deleterious mutations were identified in the tumor samples for 16 of 49 evaluable patients (32.7%). Of these, 14 patients experienced a response to olaparib (87.5%). All patients with a BRCA2 alteration responded to treatment with olaparib. Defects in ATM were indicative of response to olaparib, although, 1 patient with a type of ATM alteration did not respond to therapy. In addition to these alterations, biallelic losses in other relevant genes were seen in FANCA and CHEK2. In patients without DNA repair defects (n = 28), a response to olaparib was not observed. Researchers reported that the gene panel had a 94% specificity rate. According to Mateo, this means that 94% of patients without these mutations will be correctly identified, which will help clinicians select the correct treatment for a patient because they can be reasonably certain that olaparib will not benefit a patient who does not have these mutations. The sensitivity for the test was 87.5%. As with previous studies involving olaparib, the most common grade >3 adverse events were anemia (20%) and fatigue (12%), with 26% of patients requiring a dose reduction. The next stage of the study will seek to validate the molecular signature by enrolling only participants who test positive (NCT01682772). “For TOPARP-B, we are enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A,” Mateo confirmed.
The FDA approved olaparib as a treatment for women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy in December 2014. The drug was approved along with a companion diagnostic to identify patients with this alteration, labeled BRACAnalysis CDx. -